ES2325020T3 - PHARMACEUTICAL COMPOSITIONS. - Google Patents

Abstract

The present invention provides a solid composition for oral administration comprising: (i) a drug compound; (ii) chitosan or a derivative thereof or a salt of chitosan or salt of a derivative of chitosan; and (iii) an organic acid. Preferably the drug compound is a polar molecule having a molecular weight of 1 KDa or less, a peptide, a protein or a polysaccharide. The compositions of the invention provide enhance absorption of the drug compound.

Description

Pharmaceutical compositions

This invention relates to compositions pharmaceuticals for oral administration comprising a compound of drugs, chitosan or one of its derivatives or a chitosan salt or a salt of a chitosan derivative and an organic acid where at less part of the acid is in the form of agglomerate.

The oral route is the preferred medium for administration of drugs to people and animals due to their convenience, simplicity and acceptability on the part of patients Most of the drugs created are well absorbed by the intestine, usually by a process of passive absorption, although certain compounds are taken by more specific means as facilitated or active transport. Polar molecules small often show little or negligible absorption when dose orally. Polypeptide drugs, polysaccharides and Proteins generally cannot be administered orally by reasons of hydrophilicity, high molecular weight and susceptibility to degradation by the acidic and enzymatic environment of the tract gastrointestinal. As a consequence, with few exceptions, absorb negligible amounts of peptide compounds and proteins in the systemic circulation when administered orally. The absolute oral bioavailability of said compounds (percentage absorbed compared to the same dose supplied as intravenous injection) is generally less than 1%. A remarkable exception is cyclosporine, which is a non-polar peptide compound with a partition coefficient (octanol / water) greater than 1000.

There has been a great interest in developing new management strategies to evade the obstacles of delivery of peptide and protein drugs by the oral route. A possible strategy is to formulate the protein / peptide drug with a compound that improves the absorption of the drug through the mucous wall of the intestine.

One of these compounds is chitosan. He Chitosan is a bioadhesive polymer derived from the acetylation of chitin and comprises glucosamine units and N-acetyl glucosamine.

The use of chitosan to increase the transmucosal absorption of drug compounds is described in WO90 / 09780. Luessen et al ., (J. Control. Rel., 45, 15-23, 1997) state that the accumulation of chitosan, as an aqueous solution at pH 5.6, increased the transport of peptide compounds through monolayers of Caco-2 cells and isolated rat intestinal loop. Thanou et al ., (Pharm. Res., 18, 823-828, 2001) investigated the intestinal absorption of the peptide compound, octreotide, in pigs. The administration of an aqueous solution containing chitosan hydrochloride at pH 5.5 or trimethyl chitosan chloride at pH 7.4 produced substantial increases in bioavailability compared to an octreotide solution alone.

Shu, XZ et al , International Journal of Pharmaceutics, vol. 212, No. 1, 05.01.2001, pages 19-28, report on chitosan films cross-linked with pH-sensitive citrate. Under acidic conditions the films dilated and the model drugs were quickly released. However, under neutral to intestinal conditions the release was delayed.

The studies mentioned above used Chitosan in the form of an aqueous solution. This has a series of Disadvantages for oral administration of the peptide / protein. In In particular, the peptide / protein will come into direct contact with the gastric juice, with potentially serious consequences. The content of acid and enzyme (pepsin) from gastric juice can produce a significant degradation and loss of compound activity of peptide / protein. In addition, many peptide / protein compounds they don't have good long-term stability when they are prepared as aqueous solutions

There is a need to provide a means to oral administration of drug compounds that often do not They are successfully administered orally.

Such drugs include polar molecules. small, peptides, proteins and polysaccharides. In particular, there is  the need to provide a composition containing these drug compounds in the form of a tablet or capsule that ensure good stability, provide effective oral absorption and allow the possibility of applying acid resistant wraps to protect the drug compound from the gastric environment.

The present invention provides a composition attachable for oral administration that addresses this need.

To increase the absorption of a compound of drugs are assumed to require high local concentrations of the drug compound and a compound that improves the absorption.

Chitosan is a weak base (pKa 6.5) and an acidic environment is necessary to convert its glucosamine units into the non-helical and positively charged form soluble in water. At neutral and basic pH values, the chitosan loses its charge and precipitates from the solution, thus losing its potential bioadhesive properties and improving absorption. At higher pH values where chitosan is insoluble, rapid disintegration of tablet formulas has been recorded (Inoyatov et al , Pharm, Ind., 60, 472-475, 1998). At lower pH, where chitosan is soluble, the tablets formed a gel matrix that inhibited chitosan dissolution.

The pH of the human small intestine ranges from 5 in the jejunum to more than 7.5 in parts of the colon. Therefore there are areas of the intestine in which chitosan is soluble and areas in which it is insoluble.

If the pH is high, the chitosan will not hydrate It will ionize and the solid dosage form will quickly disintegrate. However, the chitosan will remain indissoluble and therefore will be unable to improve intestinal absorption of the drug.

If the pH is low, the chitosan will hydrate It will ionize easily. Adjacent chitosan particles are will adhere to each other with the result that the surface of the dosage forms will form a hydrated gelled layer that inhibits the penetration of water in the core of the dosage form. As a result, the chitosan will dissolve only slowly from the dose form surface.

Therefore, there is a need to produce a solid pharmaceutical composition for oral administration of which the dissolved chitosan and the dissolved drug are released quickly and simultaneously on the pH range found in the intestine so that chitosan can act to improve absorption Intestinal drug compound. We have found surprisingly, this can be achieved by incorporating an acid Organic in solid pharmaceutical preparation.

By "rapidly" we mean that the dissolution rate of the drug and chitosan using an in vitro assay as described in the Examples, is such that the time it takes to dissolve between 20% and 75% of the drug content or chitosan in a tablet or capsule is preferably less than 240 minutes, more preferably less than 210 minutes and ideally less than 180 minutes. By "simultaneously" we mean that the time difference between the dissolution of 75% of the drug content and 75% of the chitosan content of a tablet or capsule is more preferably less than 180 minutes, more preferably less than 150 minutes and the more suitable less than 120 minutes.

We have found that combining a compound of drugs with chitosan or a derivative thereof or a chitosan salt or a salt of a chitosan derivative and an organic acid in a solid composition may favor drug absorption in certain environments within the intestinal tract of animals as per example humans.

The present invention provides a composition solid for oral administration comprising:

(i)

a drug compound;

(ii)

chitosan or a derivative thereof or a salt of chitosan or a salt of a chitosan derivative; Y

(iii)

an organic acid in which at least part of the acid It is in the form of chipboard.

Chitosan is a bioadhesive biopolymer cationic comprising glucosamine and N-acetyl glucosamine With the term "chitosan" we include all chitin derivatives, or poly-N-acetyl-D-glucosamine, including all polyglucosamines and oligomers of materials from glucosamine of different molecular weights, in which the highest proportion of the N-acetyl groups has been extracted by hydrolysis (deacetylation). In accordance with this invention, the degree of deacetylation, which represents the proportion of N-acetyl groups that have been extracted by deacetylation, should preferably be in the range of 40-97%, more preferably in the range of 60-96% and most suitable is in the range of 70-95%

Chitosan, derivative or chitosan salt employed in the present invention should preferably have a molecular weight in the range of 10,000 to 1,000,000 Da, plus preferably in the range of 15,000 to 750,000 Da and the ideal is of 20,000 to 500,000 Da.

Chitosan salts and chitosan derivatives they are suitable for use in the present invention. You leave them with Several organic and inorganic acids are compatible. Such salts Compatible include, but are not limited to, nitrate salts, phosphate, glutamate, lactate, citrate, hydrochloride and acetate. The Preferred salts are those of hydrochloric acid and those of acid glutamic

Chitosan derivatives are also suitable for use in this invention. Appropriate derivatives of chitosan include, without limitation, esters, ethers for other derivatives formed by the union of acyl and / or alkyl groups with the hydroxyl groups, but not the chitosan amino groups. The examples include, chitosan O-alkyl ethers and chitosan O-acyl esters. The chitosans modified, such as polyethylene glycol conjugates can be used in the present invention. Chitosan and polyethylene glycol conjugates are described in WO99 / 01498.

Chitosans suitable for use in The present invention can be obtained from various sources, including Primex, Haugesund, Norway, FMC Biopolymer, Drammen, Norway; Seigagaku America Inc., MD, USA; Meron (India) Pvt. Ltd., India; Vanson Ltd. VA, USA; and AMS Biotechnology Ltd., United Kingdom. Appropriate derivatives include those disclosed in Roberts, Chitin Chemistry, MacMillan Press Ltd., London (1992).

Chitosan compounds particularly Preferred that may be mentioned include "ChitoClear®" Available from Primex, Haugesund, Norway.

Chitosan salts and salts of derivatives Chitosan tends to hydrate more easily than the base of Chitosan when in contact with an aqueous medium. Thus, the chitosan in the form of its free base (hereinafter referred to as "chitosan base") can preferably be used in the present invention to ensure that a gel layer is not formed too fast since this could potentially delay the solution of the solid composition containing the drug.

Any appropriate organic acid can be used. in the present invention. Appropriate organic acids include, not limited to them, those that comprise between 2 and 10 atoms of carbon, preferably 3, 4, 5 or 6 carbon atoms. Acids Suitable include lactic, glutamic, succinic acid, tartaric, citric, fumaric and propionic. The ideal organic acid It is succinic acid.

Organic acid is present in the compositions of the invention at least partially in the form of agglomerate. Preferably at least 80%, more preferably at minus 85% and ideally at least 90% of the acid is present in the form of chipboard.

With the term "agglomerate" we mean an association of particles, for example acid particles. How used here, the term "chipboard" includes particles individual such as individual acid particles made with a certain size, for example by a standard technique in the field like precipitation, atomization or crystallization.

The compositions of the invention may contain one or more agglomerate particles. Typically one way Single dose contains several particleboard particles.

The use of an agglomerate of organic acid reduces the area ratio: acid surface weight, thereby reducing the proportion of the solution. An expert you will appreciate that by adjusting the degree of agglomeration it is possible to adjust The proportion of acid dissolution. Typically, the level of acid agglomeration should be such that chitosan particles in the dosage form be able to separate and disperse before to get hydrated, thereby allowing a quick disintegration of the dosage form.

The agglomerate of organic acid can be in form of granule, pellet, tablet or acid particle made in a specific size Granules, pellets or tablets can be produced by any appropriate technique known to the experts Appropriate techniques include wet granulation, dry granulation (precompression), extrusion / spheronization, the fluid bed granulation, spray drying, freezing by sprinkling, the coating on an inert seed like the Sugar seed, compression and molding.

As you can see the person understood, to help in manufacturing the process and to produce agglomerates with the desired pharmaceutical properties, such as hardness, friability, disintegration and dissolution, may be necessary include other ingredients in acid agglomerates. It can use any additional appropriate ingredient. These include, without limiting them, diluents such as calcium phosphate, lactose, dextrose, mannitol and microcrystalline cellulose, binding agents such as povidone (polyvinylpyrrolidone), methylcellulose, polyethylene glycol, gelatin and acacia, disintegrants such as starch, croscarmellose and crospovidone, sliders such as colloidal silica, surfactants such as sodium lauryl sulfate and polysorbates, and lubricants such as magnesium stearate and vegetable oil hydrogenated

Optionally, the acid agglomerate can also be coated to modify its dissolution properties, for example to produce a small delay in dissolution that will allow the chitosan component of the dosage form to be Disperse before contacting with dissolved acid. The coatings that can achieve this effect include the water soluble, those that are insoluble but permeable to water and those that are soluble in the pH found in the small intestine. Coatings that are both water permeable and insoluble in the pH found in the small intestine are not appropriate.

The appropriate coating materials include polymers such as povidone, polyethylene glycol, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, sucrose, ethyl cellulose, copolymers of methacrylic acid such as Eudragits L and S (registered trademarks of Rohm Pharma, Darmstadt, Germany), ammonium methacrylate copolymers such as Eudragits RL and RS, cellulose acetate phthalate, cellulose acetate butyrate, phthalate of hydroxypropylmetacellulose and lacquer. The preferable polymers are those that are soluble in the environment of the small intestine, in Particularly povidone, polyethylene glycol, hydroxypropylmetacellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, alcohol polyvinyl, sucrose, methacrylic acid copolymers, phthalate cellulose acetate, butyrate cellulose acetate and phthalate hydroxypropyl methylcellulose.

The coating material can optionally include one or more additives, for example a plasticizer such as triacetin or the phthalate or polyethylene glycol ester, an agent non-stick such as talc or magnesium stearate or silica colloidal, an antifoaming agent and a dye. Other additives appropriate will be apparent to the person specialized in technique.

The acid agglomerate can be coated using standard techniques in the field. The techniques Suitable include spraying an aqueous solution or organic, for example using a bed cover fluidized, tray coater or drum coater. He thickness of the coating layer will depend on the properties of the chosen coating material, but will typically be in the range of 1-100 µm.

The size of the acid agglomerate must be large enough that the dissolution rate of the acid is reduced compared to that of the non-agglomerated acid, but at the same time small enough to allow the preparation of an acceptable drug compound. For example, if the acid agglomerate is too large, problems may arise to produce a uniform mixture with the other components of the dosage form, especially if these other components have a much smaller particle size. The preferred average particle size of the acid agglomerate, measured by the granulometric analysis, is 0.1 to
5 mm, more preferably 0.15 to 3 mm and most suitable is 0.2 to 2 mm, for example about 0.5 mm. Granulometric analysis is described in "Particle size analysis in pharmaceutics and other industries. Theory and Practice", Chapter 3, C. Washington, Ellis Horwood, Chichester, 1992.

The amount of acid is chosen to get a rapid dissolution of the chitosan present in the composition. The Acid weight ratio: chitosan (calculated based on amount of chitosan or derivative or chitosan salt or salt of a chitosan derivative) in the composition of the invention is preferably in the range of 10: 1 to 1: 1, more preferably in the range of 8: 1 to 1: 1 and the most suitable range is 6: 1 to 1: 1.

The drug compound used herein invention can be any drug compound for which greater absorption is required when administered by route oral. Such drug compounds include small molecules polar (such as those with a molecular weight of 1 KDa or less), peptides, proteins and polysaccharides.

By the term "polar molecule" we want say molecules that have a partition coefficient between water  and octanol at pH 7.4 of less than 10.

Examples of drug compounds of molecules Small polar include bisphosphonates such as clodronate, alendronate, etidronate, pamidronate and residronate, drugs nucleoside analog antivirals such as acyclovir, and oligonucleotides Examples of therapeutic peptides include octreotide, insulin, glucagon, calcitonins such as calcitonin Salmon, parathyroid hormone and derivatives such as PTH 1-34, ADH (vasopressin) and analogues such as desmopressin, and GnRH agonists such as leuprolide and goserelin. Examples of therapeutic proteins include the hormone of growth, interferons, erythropoietin, interleukin, GM-CSF and G-CSF. Examples of therapeutic polysaccharides include heparin and heparins of Low molecular weight such as enoxaparin, dalteparin, reviparin and tinzaparin

The compositions of the invention may contain more than one compound of drugs. In this situation it is not it is necessary that each drug be a compound for which it requires increased absorption when administered orally.

As you can see the person understood in the field, the amount of drug compound incorporated into the compositions of the invention will depend on a number of factors as the proposed dose regimen and the strength of the drug. The amount of drug compound incorporated in the compositions of the invention will generally be in the range of 0.001 mg at 1000 mg

The compositions of the invention may occur in several different ways. The following are examples  of steps that can be used in the production of the compositions of the invention.

(i)

The drug compound can be mixed with chitosan or a derivative thereof or a chitosan salt or a salt of a derivative of chitosan and organic acid, which can, by example, be in the form of an agglomerate of acid.

(ii)

The drug compound can be incorporated into agglomerated with organic acid, which are then mixed with chitosan or a derivative thereof or a chitosan salt or a salt of Chitosan derivative.

(iii)

The drug compound can be formed in agglomerates, which are then mixed with organic acid, which it may be in the form of agglomerates, and chitosan or a derivative of this or a chitosan salt or a salt of a derivative of chitosan

(iv)

The drug compound can be formed in agglomerated with chitosan or a derivative thereof or a salt of chitosan, or a salt of a chitosan derivative, which is mixed then with organic acid, which can be in the form of agglomerates

The mixtures produced using the steps described above may be subject to standard tablet formation or can be put in capsules.

The compositions of the invention are solid. They can be presented as a compressed tablet, tablets molded and hard or soft cover capsules. The capsules can be made of any material like jelly, hydroxypropyl methylcellulose or starch. The capsules may contain one or more tablets, powders, granules or pellets.

The compositions of the invention may also contain other acceptable pharmaceutical ingredients such as, without limited to them, diluents such as calcium phosphate, lactose, dextrose, mannitol and microcrystalline cellulose, accumulators such as povidone (polyvinylpyrrolidone), methylcellulose, polyethylene glycol, gelatin and acacia, disintegrants such as starch, croscarmellose and crospovidone, sliding like colloidal silica, surfactants such as sodium lauryl sulfate and polysorbates, and lubricants such as magnesium stearate and the hydrogenated vegetable oil, dyes and flavorings or others agents generally used in solid pharmaceutical preparations and well known to those skilled in the art.

The weight of the compositions of the invention when it is in the form of tablets or capsule it is typically 50 to 2000 mg The combined amount of chitosan and acid in the tablet or capsule will typically be in the range of 10 to 80% of the weight of the composition (calculated based on the amount of chitosan or derivative or chitosan salt or salt of a chitosan derivative). The rest of the composition will comprise the compound of drugs and others pharmaceutically acceptable ingredients.

The compositions of the invention can be used for oral administration of thought drug compounds to exercise a systematic action or a local action in the place where the drug is released.

In a preferred aspect of the invention, the compositions of the invention can be coated with a material that protect the composition of gastric contents, and thus prevent to the drug and chitosan or its derivative or a chitosan salt or a salt or a chitosan derivative of being released until the dosage form reaches the target site for the absorption of drug, for example the intestines. Delivery in place specific, for example inside the intestines, is achieved conveniently by the application of a coating sensitive to pH that is insoluble in gastric pH but soluble in the pH of target site Such coatings are also known as enteric coatings. Examples of pH coatings suitable include methacrylic acid copolymers and methyl methacrylate copolymers such as Eudragit (brand Registered from Rohm Pharma, Darmstad, Germany) L and S series, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate and lacquer. Other coatings suitable are those described in WO98 / 15265, for example.

The thickness of the coating layer will depend of the properties of the chosen coating material, but It will typically be in the range of 10-200 µm.

Enteric coating polymer layer may optionally include one or more additives, for example a plasticizer such as triacetin or phthalate or polyethylene glycol ester, a nonstick agent such as talc or magnesium stearate or colloidal silica, an antifoaming agent and a dye. Others Appropriate additives will be readily apparent to the person of an ordinary skill in the trade.

Enteric coating can be applied using standard techniques such as spray coating of an organic solvent based or water based preparation within solid dose form on a tray, drum or bed set fluidized coating.

The present invention also provides the use chitosan or a derivative thereof or a chitosan salt or a salt of a chitosan derivative and an organic acid to enhance the absorption of a drug compound that is a polar molecule with a molecular weight of 1 KDa or less, a peptide, a protein or a polysaccharide, after oral administration of the drug.

The present invention also provides the use of chitosan or a derivative thereof or a chitosan salt or a salt of a chitosan derivative and an organic acid in the manufacture of a medication for oral administration of a drug compound which is a polar molecule with a weight of 1 KDa or less, a peptide, a protein or a polysaccharide.

The present invention also provides a method for the administration of the drug compound which is a polar molecule with a molecular weight of 1 KDa or less, a peptide, a protein or a polysaccharide, which comprises the administration of a composition of the invention to the patient orally.

The compositions of the invention can be used to treat / prevent diseases / conditions in mammalian patients dependent on the therapeutic agent (s) that is used (n). For the above, the lists do not exhaustive drugs, diseases / conditions that may be mentioned, including those against which it is known that Therapeutic agents in question are effective, include lists made specifically for the drugs in question in Martindale "The Extra Pharmacopoeia", 33rd Edition, Royal Pharmaceutical Society (2002).

The compositions of the invention have the advantage that, after oral administration, they can provide a increased absorption of drugs that are generally not well absorbed when they are administered by the oral route.

In the Figures:

Figure 1 shows the chitosan solution of capsule formulations at pH 7.2 with time.

Figure 2 shows the detachment of the sodium salicylate capsule formulations at pH 7.2 with weather.

Figure 3 shows the chitosan solution of capsule formulations at pH 5.6 over time.

Figure 4 shows the detachment of the sodium salicylate capsule formulations at pH 5.6 with weather.

Figure 5 shows the chitosan solution and the release of sodium salicylate from the formulation of the tablet inside the capsules of pH 7.2 and pH 5.6 with time.

The invention is illustrated with the following non-limiting examples

Examples Example 1 Preparation and dissolution test of chitosan tablets

A powder mixture was prepared by mixing 20 grams of chitosan (ChitoClear® Primex, Haugesund, Norway) and 80 grams of mannitol (Pearlitol SD200, Roquette, Lestrem, France). He chitosan had a degree of deacetylation of 93% and a weight Average molecular weight of approximately 200,000 Dm. The powder mixture is compressed using a Manesty F3 tablet press (from Manesty, Liverpool, United Kingdom) equipped with 9 mm circular tool diameter to produce tablets.

The dissolution of the tablets was measured in a HEPES buffer solution pH 7.4 at 37 ° C using Method II of the United States Pharmacopeia (USP26 / NF21, United States Pharmacopeia Convention, Rockville, MD, USA, 2002) with blades at 100 rpm. Be they used 250 ml of buffer solution in each beaker of dissolution.

Samples were removed from the dissolution medium at periodic intervals up to 240 minutes, they were filtered (0.45 µm) and the chitosan content was measured using an assay of ninhydrin.

To perform the chitosan assay, it was prepared first a 10 ml buffer solution of lithium acetate dissolving 4.08 grams of lithium acetate in approximately 6 ml of water, adjusting the pH to 5.2 with acetic glacier acid and providing up to 10 ml of water. The ninhydrin reagent was made adding 10 ml of lithium acetate buffer solution to 0.8 g of ninhydrin and 0.12 g of hydrindantin in 30 ml of DMSO. They were added 0.5 ml of this reagent to 0.5 ml of the dissolution sample of a Vial flashing vial. The vial was capped, shaken briefly and It was heated in boiling water for 30 minutes. After cooled, 15 ml of a mixture of ethanol: 50:50 water was added to each vial and the vortex of the content was mixed for 15 seconds.  The absorbance of each solution at 570 nm was measured and the Chitosan concentration in the sample with a curve of standard calibration

In the dissolution test, the tablets Chitosan disintegrated almost immediately. However, the insignificant amounts of chitosan were tested in the medium of dissolution (<5% of the chitosan present had dissolved) i.e. although the chitosan quickly detached itself from the tablets, It did not dissolve.

Example 2

Preparation of succinic acid / sodium salicylate pellets

220 grams of microcrystalline cellulose (Avicel PH101, FMC, Philadelphia, USA), 200 grams of succinic acid (Sigma) and 20 grams of sodium salicylate (Fluka, Buchs, Switzerland) are They added to the bowl of a Kenwood blender. The mixture was beaten for 3 minutes at 60 rpm. Water was added gradually while It was mixed to granulate the mixture. When the granulate was estimated that had achieved an appropriate consistency for extrusion (230 ml of water added), stopped adding and mixing continued for another 10 minutes more. The material was extruded using Caleva Model extruder. 10 (Caleva, Sturminster Newton, Dorset, Kingdom United) at 15 rpm. The diameter of the holes in the extruder was 1 mm The extruded mixture was then spheronized in batches of Approximately 45 grams using Caleva Model spheronizer. 120 (Caleva, Sturminster Newton, Dorset, United Kingdom) for 10 minutes set to 75 (2250 rpm). The balls dried during the overnight in an oven at 50 ° C. The final yield of dried pellets was of 359 grams.

Example 3

Preparation of balls of succinic acid / sodium salicylate coated

150 ml of water was heated to approximately 80 ° C 10 grams of hydroxypropyl methylcellulose was poured (Methocel E5LV, Colorcon, Orpington, UK) in the water hot. The dispersion was cooled in an ice bath while stir to form a clear solution. The solution was made with Up to 200 ml of water.

The balls produced in Example 2 were screened and the fraction between 0.71 and 1.00 mm (251 grams) 200 grams of these balls were put inside the chamber of coating an Aeromatic fluidized bed coater STREA-1 (lower spray) (Niro Aeromatic, Bubendorf, Switzerland). The Methocel solution was applied to the balls to a coating temperature of 60 ° C and a proportion of application of 1.5 grams per minute. 175 ml of the coating solution giving a theoretical HPMC content to the final balls of 4.4% w / w.

Example 4

Capsules containing chitosan, succinic acid powder and sodium salicylate powder

3,125 grams of chitosan, 6.25 were weighed grams of succinic acid and 0.625 g of sodium salicylate and it transferred to a poly bag. The powders mixed Shaking the bag and its contents. A sample of 320 mg of mixture weighed in each of 3 hard gelatin capsules of size 0 (Capsugel, Basel, Switzerland).

Example 5 Capsules containing chitosan and acid balls uncoated sodium succinic / salicylate

7.8125 grams of chitosan, 7.8125 grams of Mannitol and 34,375 grams of sodium / acid salicylate pellets succinic described in Example 2 were weighed and transferred to a poly bag. The ingredients were mixed by stirring the bag and its contents. A sample of 640 mg of the mixture was weighed into each of 3 hard gelatin capsules in size 0.

Example 6 Capsules containing chitosan and acid balls coated succinic / salicylate

7.583 grams of chitosan, 7.583 were weighed grams of mannitol and 33,834 grams of acid balls coated succinic / sodium salicylate described in Example 3 and transferred to a poly bag. The ingredients are mixed by shaking the bag and its contents. A sample of 659 mg of the mixture was weighed into each of 3 hard capsules of Jelly size 0.

Example 7 Dissolution of chitosan / salicylate formulations of sodium / succinic acid

The dissolution of the formulations was evaluated as as described in Example 1. In addition to the content of chitosan, in the samples of the dissolution medium also analyzed the content of sodium salicylate by measuring the UV absorbance at 297 nm and sending it to the calibration curve (sodium salicylate in HEPES pH 7.4 regulator in a range of concentration of 0.1 to 1 mg / ml). In addition, the dissolution test is also performed on an acetate regulator pH 5.6.

The dissolution data are given in the Figure 1 (chitosan, pH 7.2), in Figure 2 (sodium salicylate, pH 7.2), in Figure 3 (chitosan, pH 5.6) and in Figure 4 (sodium salicylate, pH 5.6).

Figures 1 and 2 illustrate a rapid dissolution both chitosan and the model drug compound (sodium salicylate) of capsules in which the acid was incorporated as uncoated and coated pellets (Examples 5 and 6 respectively). On the contrary, the dissolution of both chitosan as the drug was slow when formulated as a capsule with acid in powder form (Example 4).

A similar dissolution pattern was observed in pH 5.6 (Figures 3 and 4).

Example 8 Tablets comprising succinic acid / salicylate pellets coated sodium, chitosan and mannitol contained within capsules

2,388 grams of chitosan, 10,932, were weighed grams of the coated pellets produced in Example 3 and 6.68 g of mannitol and transferred to a polythene bag. The Ingredients were mixed by shaking the bag and its contents. A Manesty F3 tablet press was equipped with concave punches 6 mm rounded normals. To lubricate the punches rubbed manually with magnesium stearate (Merck Chemicals, Poole, United Kingdom). The tablets were compressed from mixing in powder at a target weight of 140 mg and a target hardness of 4-8 kp. Six tablets were placed in a capsule hard jelly size 0. The solution was analyzed as described in Example 1, with 250 ml of pH 5.6 or pH 7.2 regulator As a test medium. Three capsules were analyzed in each glass of dissolution and a triplicate analysis was performed. The Chitosan concentrations were measured using the assay of ninhydrin described in Example 1. Concentrations of Sodium salicylate were measured by UV absorbance at 297 nm.

As Figure 5 shows, there was a release rapid and simultaneous drug and chitosan in both pH 5.6 and at pH 7.2.

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References cited in the description This list of references cited by the applicant Its sole purpose is the convenience of the reader. It is not part of European Patent document. Although great care has been taken in the compilation of references, errors cannot be excluded or omissions and the EPO rejects any responsibility in this sense. Patent documents cited in the description

WO 9009780 A

WO 9901498 A

WO 9815265 A

Non-patent related literature cited in the description

LUESSEN et al. J. Control. Rel ., 1997 , vol. 45, 15-23

THANOU et al. Pharm Res ., 2001 , vol. 18, 823-828

SHU , XZ et al. International Journal of Pharmaceutics , 05 January 2001, vol. 212 (1), 19-28

INOYATOV et al. Pharm Ind ., 1998 , vol. 60, 472-475

ROBERTS , CHITIN. Chemistry MacMillan Press Ltd , 1992

MARTINDALE . The Extra Pharmacopoeia. Royal Pharmaceutical Society , 2002

Claims (20)

1. A solid composition for administration oral comprising:

(i)

a drug compound;

(ii)

chitosan or a derivative thereof or a salt of chitosan or a salt of a chitosan derivative; Y

(iii)

an organic acid where at least part of the acid It is in the form of chipboard.

2. A composition according to the claim 1, wherein the acid is lactic acid, glutamic acid, succinic, tartaric, citric, fumaric or propionic. 3. A composition according to the claim 2, wherein the acid is succinic acid. 4. A composition according to the claim 1, wherein the acid agglomerate is in the form of granule, pellet, tablet or acid particle made with a determined size. 5. A composition according to any one of the preceding claims, wherein the acid agglomerate It is coated with a material that modifies its properties of dissolution. 6. A composition according to any one of the preceding claims, wherein the chitosan is present in the form of chitosan base. 7. A composition according to a any of the preceding claims, wherein the compound of drugs is a polar molecule that has a molecular weight of 1 KDa or less, a peptide, a protein or a polysaccharide. 8. A composition according to the claim 7, wherein the drug compound is a bisphosphonate, a nucleoside analog antiviral drug or an oligonucleotide. 9. A composition according to the claim 8, wherein the bisphosphonate is clodronate, alendronate, etidronate, pamidronate or residronate. 10. A composition according to the claim 8, wherein the analogue nucleoside antiviral drug is acyclovir 11. A composition according to the claim 7, wherein the peptide is octreotide, insulin, glucagon, a calcitonin, a parathyroid hormone or a derivative of this, ADH (vasopressin) or an analogue thereof or an agonist of GnRH 12. A composition according to the claim 7, wherein the protein is a growth hormone, an erythropoietin, an interferon, an interleukin, GM-CSF or G-CSF. 13. A composition according to the claim 7, wherein the polysaccharide is heparin or a heparin Low molecular weight. 14. A composition according to a any of the preceding claims, wherein the acid and the Chitosan are present in a 6: 1 weight ratio up to 1: 1. 15. A composition according to a any of the preceding claims coated with a material that prevents the drug compound and chitosan or a derivative thereof or a chitosan salt or a salt of a derivative of chitosan is released, after administration, until the composition reaches the destination of absorption of the drug. 16. A composition according to a any of the preceding claims in tablet form tablet, molded tablet, hard wrap capsule or capsule Soft wrap. 17. The use of chitosan or a derivative thereof or a chitosan salt or a salt of a chitosan derivative and a organic acid, where at least part of the acid is in the form of agglomerated, to favor the absorption of a compound of drugs which is a polar molecule that has a molecular weight of 1 KDa or less, a peptide, a protein or a polysaccharide, after oral administration of the drug. 18. A composition according to the claim 1 or any of claims 8 to 16 when dependent on claim 7, to be used for the purpose of improving drug absorption after administration oral.

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19. The use of chitosan or a derivative thereof or a chitosan salt or a salt of a chitosan derivative and a organic acid, where at least part of the acid is in the form of agglomerated, in the manufacture of a medicine for oral administration of a drug compound that is a molecule polar having a molecular weight of 1 KDa or less, a peptide, a protein or a polysaccharide. 20. A procedure to prepare a composition according to any one of the claims of  1 to 17, a process that includes:

(i)

mix the drug compound with chitosan or a derivative thereof or a chitosan salt or a salt of a derivative of chitosan and an acid; or

(ii)

incorporate the drug in agglomerates with the acid and mix the agglomerates with chitosan or a derivative thereof or a chitosan salt or a salt of a chitosan derivative; or

(iii)

form agglomerates of the drug compound and mix these agglomerates with the acid and chitosan or a derivative of this or a chitosan salt or a salt of a derivative of chitosan; or

(iv)

form agglomerates of the drug compound with chitosan or a derivative thereof or a chitosan salt or a salt of a chitosan derivative and mix these agglomerates with the acid.